Summary: Amyloid-? peptide (A?) fibrilization and deposition as ?-amyloid is a hallmark Alzheimer's disease (AD) pathology. We recently reported A? is an innate immune protein and the peptides expression protects against fungal and bacterial infections in transgenic mouse (5XFAD), nematode, and cell culture models, doubling host survival in some cases. However, fibrilization pathways mediate A?'s antimicrobial activities. Thus, infection can dramatically accelerate ?-amyloid deposition. In this new application we propose to further characterize the emerging role A? fibrillization plays in brain immunity. Our study will test if viral infection can exacerbate ?-amyloid deposition and promote tauopathy in brain. Our study will focus on A? fibrillization mediated by infection with herpesviridae viruses, including herpes simplex virus 1 (HSV1), and human herpesvirus 6A (HHV6A) and 6B (HHV6B). Herpesviridae are ubiquitous and persistent (lifelong) neurotropic human pathogens. Published data also links CNS HSV1 infection with increased ?- amyloid deposition in AD brain. While HSV1 activation is episodic, HHV6 infection is chronic with lifelong low persistent viral replication. Experiments will test ?-amyloid deposition in response to chromic long-term HHV6 and acute HSV1 infections. Experiments will characterize the protective and potentially harmful consequences of A?'s antimicrobial activities in 5XFAD mice and a 3-dimensional human stem cell-derived neural (3D-HSCDN) cell culture system. For HHV6 experiments, a novel 5XFAD mouse model will be generated that expresses human CD46, the HHV6A host cell receptor. The humanized-CD46 5XFAD mice will be used to follow ?-amyloid generation with chronic HHV6A infection over six months. In preliminary experiments, acute HSV1 encephalitis in 5XFAD mice induced extensive ?-amyloid deposition that co- localized with anti-virus signal. Infection with HSV1, HHV6A, or HHV6B also seeded ?-amyloid deposition and generated virus/?-amyloid deposits in 3D-HSCDN cell cultures. Consistent with fibrillization mediated A? AMP activity, 5XFAD mice and transformed host cells showed increased survival with herpes infection compared to low A?-expressing controls. Preliminary data from in vitro binding-ELISAs suggest selective and specific binding of soluble A? oligomers to herpes glycoprotein B mediates herpesviridae targeting. Our 3D neuronal cell culture model recapitulates both AD ?-amyloidosis and neurofibrillary tangle (NFT) generation. NFTs are a second key AD pathology. Our study will also test if herpes-induced ?-amyloid deposition leads to NFT generation. If confirmed, our model would for the first time serially link, immunochallenge, ?-amyloid deposition, and tauopathy. We believe our proposed study will add significantly to an emerging model of a protective/harmful duality to A?'s activities in brain, as well as better inform current and future AD therapeutic strategies aimed at preventing pathological A? accumulation.